Treating a variety of pathological conditions, including spasticity and convulsions, by effecting a modulation of CNS activity with isovaleramide, isovaleric acid, or a related compound

ABSTRACT

Preparations and extracts of valerian, as well as isovaleramide, isovaleric acid, and certain structurally related compounds exhibit clinically significant pharmacological properties which implicate a treatment for a variety of pathological conditions, including spasticity and convulsions, which are ameliorated by effecting a modulation of CNS activity. The compositions in question generally are non-cytotoxic and do not elicit weakness or sedative activity at doses that are effective for the symptomatic treatment of such pathological conditions.

[0001] This application is a continuation-in-part of PCT applicationPCT/US97/15272, filed Aug. 29, 1997, which was a continuation ofapplication Serial No. 60/025,050, filed Aug. 30, 1996.

BACKGROUND OF THE INVENTION

[0002] The present invention provides methods of treating pathologicalconditions, such as spasticity and convulsions, the symptoms of whichare alleviated by a modulation of activity in the central nervous system(CNS), without producing undesirable excessive sedation or muscleweakness in animal subjects, including humans. More particularly, theinvention relates to the therapeutic use of isovaleramide, isovalericacid, and related compounds in patients suffering from pathologies ofthis nature.

[0003] A number of pathological states, diseases, and disorders arecharacterized by a profound aberration in the normal function of thecentral nervous system (CNS). Such conditions include spasticity,strokes, spinal cord injuries, chronic neurodegenerative disorders anddiseases such as Parkinson's and Huntington's diseases, Alzheimer'sdisease, and epilepsy. At the clinical level, these states usually onlyrespond to pharmacologic intervention with compounds or substances thatpossess significant activity at the level of the CNS.

[0004] Many agents currently employed in the treatment of pathologiessuch as spasticity and convulsions display troubling side-effectprofiles which limit their long-term clinical utility. Among theseagents, for example, are the benzodiazepines, which can cause impairmentof cognition (impairment of memory-related performance, or “cognitiveblunting”). See, for example, ANTIEPILEPTIC DRUGS, Fourth Edition, (Levyet al, eds.), Raven Press, (1995). Two other clinically used agents arevalproate and related therapeutically useful salts such as valproic acidhemisodium salt, which are hepatotoxic and teratogenic, and baclofen,which produces excessive muscle weakness and sedation. Theseside-effects severely limit the therapeutic potential for both drugs. Itis apparent, therefore that improved and better-tolerated treatments forspasticity, convulsions, and other therapeutic indications are greatlyto be desired.

SUMMARY OF THE INVENTION

[0005] Accordingly, it is an object of the present invention to providea therapeutic approach for the treatment of various pathologies byeffecting a modulation of CNS activity without producing excessivesedation, muscle weakness, fatigue, teratogenicity or hepatotoxicity.

[0006] It also is an object of the present invention to provide a methodfor alleviating one or more symptoms associated with a condition, suchas spasticity, that is ameliorated by means of a centrally mediateddecrease in muscle tone.

[0007] It is another object of the present invention to provide a novelanticonvulsant therapy.

[0008] It is another object of the present invention to provide a novelprophylactic therapy for migraine and other headache pathologies.

[0009] It is another object of the present invention to provide a noveltherapy for affective mood disorders such as bipolar disorder.

[0010] It is another object of the present invention to provide a novelneuroprotective therapy.

[0011] It is another object of the present invention to provide a noveltherapy to assist with substance withdrawal therapy and the substancecravings that often accompany such abuse.

[0012] In accomplishing these and other objectives, there has beenprovided, according to one aspect of the present invention, a method ofusing a compound selected from the group consisting of isovaleramide, apharmaceutically acceptable ester of isovaleric acid, a pharmaceuticallyacceptable amide of isovaleric acid, and a compound selected from thegroup consisting of 2-methyl isovaleramide, 3-methylisovaleramide,2,2-dimethylisovaleramide, 2,3-dimethylisovaleramide,4-methylisovaleramide, 2,4-dimethylisovaleramide,3,4-dimethylisovaleramide, 2,2,4-trimethylisovaleramide,3-hydroxyisovaleramide, 4-hydroxyisovaleramide,4-hydroxy-3-methyl-isovaleramide, 2-hydroxyisovaleramide,N-(2-acetamido)isovaleramide, 2-methyl-1-propyl sulfonamide,1-methylethyl sulfamate, 2-methyl-1-propyl sulfamate, isopropylcarbamate, and isobutylcarbamate.

[0013] Thus, the present invention also provides a method of treatmentcomprising the step of administering, to a patient suffering from apathology that is ameliorated by a modulation of CNS activity, atherapeutically effective amount of a pharmaceutical formulationcomprising a pharmaceutically acceptable carrier and a compositionselected from the aforementioned group of agents.

[0014] According to one embodiment of the invention, thepharmaceutically acceptable amide of isovaleric acid is selected fromthe group consisting of isovaleramide, N-ethyl isovaleramide, N-methylisovaleramide, N,N-dimethyl isovaleramide, N-methyl,N-ethylisovaleramide, N-(2-acetamido)isovaleramide (“N-isovalerylglycinamide”), and N-isovaleryl GABA.

[0015] According to yet another embodiment of the invention, the treatedpathology is an affective mood disorder, convulsions, a centralneuropathic pain syndrome, a headache, or a restlessness syndrome. Instill another embodiment, the pathology is spasticity that isameliorated by a centrally mediated decrease in muscle tone. In afurther embodiment, the treated pathology is a cerebral insult,neurodegeneration, or the acquisition of epilepsy. For still anotherembodiment, the treated pathology is substance abuse, craving ofsubstance, addiction, and withdrawal.

[0016] In accordance with another aspect of the present invention, amethod of use is provided for an extract of Valerianaceae, cramp bark,black haw, or hops in a method of treating a symptom of spasticity,where the extract comprises at least one compound that is hydrolyzed invivo to yield isovaleric acid or isovaleramide. By the same token, thepresent invention provides a method for alleviating a symptom ofspasticity in a subject in need of such treatment, comprising the stepof administering a therapeutically effective amount of an extract asdescribed above.

[0017] Other objects, features, and advantages of the present inventionwill become apparent from the following detailed description. It shouldbe understood, however, that the detailed description and the specificexamples, while indicating preferred embodiments of the presentinvention, are given by way of illustration only, since various changesand modifications within the spirit and scope of the invention willbecome apparent to those skilled in the art from this detaileddescription.

BRIEF DESCRIPTION OF THE DRAWINGS

[0018]FIGS. 1a and 1 b depicts the structures of compounds, includingisovaleramide, capable of inducing a modulation of the central nervoussystem.

[0019]FIG. 2 portrays the effect of isovaleramide (at 300 mg/kg, i.p.)on gross observational spasticity scores elicited by a metal probeapplied to the abdomen in the chronic spinalized rat. Each rat served asits own control; there were three rats per group. The bar at time zerorepresents pre-treatment control values.

[0020]FIG. 3 illustrates a time-dependent reduction of the flexorreflex, an electrophysiological measure of spasticity, in the chronicspinalized rat. The effects of isovaleramide (300 mg/kg p.o.), baclofen(10 mg/kg s.c.), and vehicle (water, 12 ml/kg p.o.) are shown atpre-treatment (time zero) and at 30, 60, 90, and 120 minutespost-administration. Isovaleramide caused a significant decrease in themagnitude of the flexor reflex, comparable to that observed withbaclofen.

[0021]FIG. 4 shows a dose-response relationship for isovaleramide andbaclofen, a known antispasticity agent. Isovaleramide and baclofenproduced a similar dose-dependent reduction of the flexor reflex in thechronic spinalized rat. The responses from FIG. 3 and response fromadditional doses were converted to a total-area-under-the-curve for thetwo-hour measurement. All drug-related groups were significantlydifferent from the vehicle (p<0.05, ANOVA).

[0022]FIG. 5 shows that isovaleramide was effective in reducing in adose-dependent manner the generalized seizure responses of fully kindledrats. Isovaleramide decreased the mean seizure score and theafterdischarge duration in amygdala-kindled rats, showing that it exertsanticonvulsant activity against both focal and secondarily generalizedseizures.

[0023]FIG. 6 illustrates the antiepileptogenesis effect of a daily 500mg/kg p.o. dose of isovaleramide compared to controls. Isovaleramideelicited a delay in the rate of increase in both seizure score andafterdischarge duration (not shown) which normally develop duringelectrical kindling in the amygdala-kindled rat.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] 1. Overview

[0025] Isovaleric acid and its pharmaceutically acceptable salts, amidessuch as isovaleramide, and alcohol esters such as ethyl isovalerate andglyceryl triisovalerate can be administered in vivo to effect amodulation of CNS activity. A series of structurally related compoundsalso display similar properties. These agents modulate CNS activity byenhancing inhibitory (or decreasing excitatory) neurotransmissioncentrally, without complete suppression of all activity. Pursuant to thepresent invention, therefore, a subject receiving such an agent is notovertly sedated, anesthetized, or paralyzed in the context, for example,of decreasing seizures (while causing little or no anesthesia),decreasing muscle tone (while causing little or no accompanyingparalysis), eliciting a calmative effect (with little or no sedation),or ameliorating an ambulatory syndrome such as spasticity (with littleor no accompanying weakness or flaccidity).

[0026] A number of pathologies, exemplified by affective mood disorders(i.e. bipolar disorder), headaches (chronic, cluster, migraine),restlessness syndromes, neuropathic pain, movement disorders,spasticity, convulsions, cerebral insult, neurodegeneration, andsubstance abuse have at least one symptom that is usefully alleviated byeffecting a modulation of CNS activity. Accordingly, an individual whosuffers from such a pathology may be treated with a therapy where,pursuant to the present invention, that individual receives apharmaceutical formulation of isovaleramide, isovaleric acid, or arelated compound.

[0027] Without wishing to be bound by any theory, the inventors believethat the compounds of the present invention act via a GABAergicmechanism and, hence, bear a pharmacological similarity to known drugsthat are considered to enhance central GABAergic neurotransmission. Likemany of the extant drugs, such as the barbiturates, the benzodiazepines,gabapentin, valproic acid and therapeutically useful valproate saltssuch as valproate hemisodium salt (herein included with reference tovalproate), vigabatrin, and progabide, the compounds of the presentinvention are effective in treating pathological conditions, illustratedby those mentioned above, that are thought to arise from a defect in theregulation of inhibitory (GABA- and/or glycine-related)neurotransmission.

[0028] This regulation may occur by a direct or modulatory effect at CNSreceptors or by impact on a metabolic pathway which heightens GABA orglycine levels and/or which reduces levels of an excitatoryneurotransmitter like glutamate. See Ruggero et al., in ANTIEPILEPTICDRUGS (4th ed.), pages 581-88 (Raven Press 1995); Nogrady, MEDICINALCHEMISTRY: A BIOCHEMICAL APPROACH (2d ed.), pages 225-39 (OxfordUniversity Press 1988); Fonnum and Morselli, respectively, inPSYCHOPHARMACOLOGY: THE THIRD GENERATION OF PROGRESS, pages 173-82 and183-95 (Raven Press 1987).

[0029] Despite an anticipated similarity in mechanism of action, thecompounds of the present invention do not engender the disadvantageousside effects associated with conventional drug therapies in this area,such as the hepatotoxicity or teratogenicity that arises with valproateadministration.

[0030] 2. Exemplary Pathologies Ameliorated by a Modulation of CNSActivity

[0031] SPASTICITY: Spasticity may be “defined as an upper [i.e., CNS]motor neuron disorder characterized by a velocity-dependent increase intonic stretch reflexes (muscle tone) with exaggerated tendon jerksresulting from hyperexcitability of the stretch reflex.” Lance, Symposiasynopsis in SPASTICITY—DISORDERED MOTOR CONTROL, Feldman et al. (eds.)(1980) (Symposia Specialists, distributed by Year Book MedicalPublishers). An increase in tonic stretch reflexes, however, is only oneof the many symptoms present in a disordered motor function caused by anupper neuron lesion in a variety of neurological disorders; thus, such adisordered motor function is variable in its etiology and presentation.

[0032] Major disease states and conditions associated with spasticityinclude multiple sclerosis, cerebral palsy, stroke, trauma or injury tothe spinal cord, and closed head trauma. There are “positive symptoms”that can occur with spasticity, such as the Babinski response, painfulflexor or extensor spasms, increased or exaggerated deep tendonreflexes, and clonus. Other symptoms, referred to as “negativesymptoms,” include weakness, fatigue, lack of dexterity, and paralysis.It is the combination of these positive and negative signs and symptomsthat is denoted clinically as “spastic paresis” (spastic paralysis).Pain, impairment of sleep, and various degrees of loss of general motorfunction are also associated with spasticity.

[0033] The pathological states observed in spasticity are fundamentallydifferent at the physiological level from the commonly experienced acutemuscular aches, strains, and sprains that occur from a localizedexternal insult to a particular muscle, i.e., outside of, or peripheralto, the CNS. These pathological states also are different from therelatively common involuntary spasms of smooth muscle, such as vascularspasms, bladder spasms, and bronchial spasms. Such non-spastic(non-CNS), peripheral or localized symptoms are commonly treated withso-called “antispasmodic” or “spasmolytic” agents. Such agents generallyare not useful in treating spasticity. Cedarbaum & Schleifer, “Drugs forParkinson's Disease, Spasticity and Acute Muscle Spasms,” in GOODMAN ANDGILMAN'S THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, 8th ed. [hereafterGOODMAN AND GILMAN'S], pages 463-484 (Pergamon Press 1990).

[0034] The pharmaceutical formulations employed in accordance with thepresent invention can effect a centrally mediated decrease in muscletone and, hence, are useful for the acute or chronic alleviation of oneor more symptoms of spasticity. In the context of the present invention,“spasticity” refers to a heightened tone of skeletal muscle which ismanifested by symptoms exemplified by but not limited to painful flexoror extensor spasms, increased or exaggerated deep tendon reflexes,hyperreflexia, loss of dexterity, muscular weakness, exaggerated tendonjerks, and clonus. The phrase “antispasticity agent” refers here to acomposition that is useful for the symptomatic treatment of spasticity,as demonstrated by the alleviation of at least one of the followingmanifestations of spasticity: painful flexor or extensor spasms,increased or exaggerated deep tendon reflexes, hyperreflexia, loss ofdexterity, muscular weakness, exaggerated tendon jerks, and clonus.Accordingly, the “alleviation” of spasticity refers here to thelessening of one or more symptoms of spasticity, including, but notlimited to, painful flexor or extensor spasms, increased or exaggerateddeep tendon reflexes, hyperreflexia, loss of dexterity, muscle weakness,exaggerated tendon jerks, and clonus.

[0035] Spasticity is associated with multiple sclerosis, stroke, headtrauma, spinal cord injuries, cerebral palsy, and otherneurodegenerative diseases, disorders, and conditions. Spasticity isdistinct from acute muscle spasms, which may be associated with avariety of conditions different from those leading to spasticity. Theseacute muscle spasm-causing conditions include trauma, inflammation,anxiety, and/or pain.

[0036] The difference between spasticity and acute muscle spasms isillustrated by the fact that agents useful for the treatment of musclespasms are not useful for treating spasticity associated with chronicneurological diseases. Cedarbaum & Schleifer (1990), supra. Likewise,agents used heretofore to treat spasticity associated with chronicneurological disorders have not been employed in treating acute musclespasms, except for the benzodiazepines, such as diazepam (Valium®),which are recognized also to have muscle-relaxant activity as well asanxiolytic and anticonvulsant properties. By contrast, the presentinvention achieves a centrally mediated decrease in muscle tone which,in turn, addresses the particular symptoms of spasticity.

[0037] CONVULSIVE DISORDERS: Due to the widespread availability ofreasonably predictive and experimentally accessible animal models ofconvulsant states, a number of clinically useful anticonvulsants havebeen prepared and developed. For example, see Cereghino et al.,“Introduction,” in ANTIEPILEPTIC DRUGS, 4th ed., pages 1-11 (Raven Press1995). In many patients, seizures can be controlled with currentlyavailable antiepileptic drugs, but 25 to 30 percent of patients continueto have seizures despite optimal therapy, while many others experienceunacceptable side effects. Dichter et al., Drug Therapy 334: 1583(1996).

[0038] Thus, many anticonvulsants in clinical use are plagued by theoccurrence of significant side effects, including troublesome daytimesedation, cognitive impairment, muscular weakness, tolerance, gingivalhyperplasia, blood dyscrasias, teratogenicity, and potentially fatalhepatotoxicity. Many of these side effects are especially of concern inthe clinical management (treatment) of epilepsy in children.

[0039] The present invention can be used to treat convulsive disorderssuch as epilepsy. That is, the pharmaceutical compositions of theinvention display “anticonvulsant activity,” which is evidenced by areduction of the severity, number, and/or duration of convulsions inanimal models of epilepsy. Accordingly, the inventive pharmaceuticalcompositions should be useful in treating conditions including, but notlimited to, simple partial seizures, complex partial seizures,generalized tonic-clonic seizures, secondarily generalized seizures,status epilepticus, and trauma-induced seizures, as occur following headinjury or surgery.

[0040] Epilepsy is a common disorder with many causes, and can be verydifficult to treat, often requiring treatment for many years to keepseizures under control. No satisfactory treatment for epilepsy currentlyexists in a substantial proportion of patients. Different patients oftenhave a better response to one drug than another, even when the patientshave similar types of seizures and the drugs have similar mechanisms ofaction. The frequency and severity of side effects also variessubstantially. Dichter et al. (1996), supra.

[0041] The pharmaceutical compositions of the invention display“anticonvulsant activity,” evidenced by a reduction of the severity,number, and/or duration of convulsions in animal, models of epilepsy.Accordingly, the inventive pharmaceutical compositions should be usefulin treating conditions including, but not limited to, simple partialseizures, complex partial seizures, secondarily generalized seizures,status epilepticus, and trauma-induced seizures, as occur following headinjury or surgery.

[0042] AFFECTIVE MOOD DISORDERS: Included within the rubric of affectivemood disorders are conditions ranging from depression to dysphoricmania, i.e., bipolar mood disorder, mania, schizoaffective disorder,traumatic brain injury-induced aggression, post-traumatic stressdisorder, panic states, and behavioral dyscontrol syndromes. Affectivemood disorders have been treated primarily prophylactically, withlithium salts, since the 1950s in Europe and since the 1970s in theUnited States. Emrich et al., J. Affective Disorders 8: 243-50 (1985).In recent years, alternatives to lithium treatment have been underdevelopment, given the several problems with lithium therapy. Newer,alternative therapies to lithium for affective mood disorders areanticonvulsants such as carbamazepine, benzodiazepines, valpromide, andvalproate. Bernasconi et al., in ANTICONVULSANTS IN AFFECTIVE DISORDERS,pages 14-32 (Excerpta Medica 1984). Valproate has a lower propensitytowards depressed arousal and mentation, memory impairment, andcognitive blunting than is seen with the benzodiazepines.

[0043] Despite the demonstrated efficacy of valproate in a multitude ofaffective disorders, the hepatotoxicity, teratogenicity, and gastricupset observed with its administration highlights the need for newtherapeutic agents and treatments with improved side effect profiles. Apharmaceutical formulation according to the present invention iseffective to this end, especially with respect to improved side effects.It is anticipated that isovaleramide and related compounds willdemonstrate an absence of the type of side effects that significantlydetract from the clinical usefulness of valproate. Thus, several studiesof various analogs and metabolites of valproic acid have led to definedstructural requirements for teratogenesis (Nau and Hendrickx, Atlas Sci.Pharmacol. Toxicol. 69: 310-321, (1987); Bojic, et al., Chem. Res.Toxicol. 9:866-870, (1996); Nau et al., Pharmacology and Toxicology 69:310-321, (1991); Nau, Fundamental and Applied Toxicology 6: 662-668,(1986); Nau and Scott, Nature 323: 276-278, (1986).; Hauck and Nau,Pharmaceutical Research 9: 850-855, (1992); and Nau and Loscher,Fundamental and Applied Toxicology 6: 669-676, (1986) and hepatoxicity(Tang et al., Chem. Res. Toxicol. 8: 671-682, (1995)). Valproic aciditself is teratogenic (Nau and Hendrickx, 1987). Some of the structuralelements required for teratogenic activity in vivo are: a free carboxylgroup (stable amides exhibit significantly lower teratogenicity, or tobe non-teratogenic); substituents on C-2 larger than a methyl group, anda double or triple bond at C-4. Addition of a methyl group at C-3 tovalproic acid reduces teratogenicity.

[0044] NEUROPATHIC PAIN SYNDROMES: Conditions in this category,involving “neuropathic pain,” affect a significant number of patientssuffering from disorders of the brain or spinal cord, such as stroke,trauma, multiple sclerosis, and diabetes. Casey, in PAIN AND CENTRALNERVOUS SYSTEM DISEASE (Raven 1991). Several known anticonvulsantcompounds are efficacious in various analgesia models relevant toidentifying therapeutic candidates for treating neuropathic pain. SeeLloyd & Morselli, in PSYCHOPHARMACOLOGY: THE THIRD GENERATION OFPROGRESS (Raven Press 1987). In a related vein, the use ofanticonvulsants like valproate to treat various pain states has beendocumented extensively. Swendlow, J. Clin. Neuropharmacol. 7: 51-82(1984). Thus, a pharmaceutical formulation of the present invention willbe applied in similar fashion to ameliorate neuropathic pain.

[0045] HEADACHES: Headaches of the migraine type (Hering & Kuritzky,Cephalalgia 12: 81-84 (1992)), the cluster type (Hering & Kuritzky, loc.cit. 9: 195-98 (1989)) and the chronic type (Mathew & Sabiha, Headache31: 71-74 (1991)) have been treated by the administration of valproateand other anticonvulsants. The compositions of the present inventionalso will alleviate symptoms associated with each of the three headachetypes, without the adverse side effects of valproate and otheranticonvulsant therapy.

[0046] RESTLESSNESS SYNDROME: The phrase “restlessness syndrome” denotesa somatic (non-mental) restlessness characterized by involuntarymovement of the limbs, as well as by a sense of physical (rather thanmental) agitation, which is independent of mood and, hence, isdistinguished from restlessness per se. See Sachdev et al., Austral. NewZealand J. Psychiatry 30: 38-53 (1996).

[0047] The genus of restlessness syndromes, inclusive of numerousindications, can be observed in association with many organic andnon-organic psychiatric illnesses. For example, drug-inducedrestlessness (tardive, chronic, and withdrawal akathisias), such asdrug-induced extrapyramidal symptoms, is one of the most common sideeffects of neuroleptic drug therapy. Also within therestlessness-syndrome rubric are the so-called “restless leg syndrome”and “sleep-related periodic leg movements,” pathologies that can beassociated with head and/or spinal cord trauma and with lesions of thespinal cord. Idiopathic restless leg syndrome follows an autosomaldominant inheritance, with a variable clinical expression of symptoms.

[0048] Diminished GABAergic neurotransmission is implicated in theneurochemical basis of restlessness syndromes. Consistent with thisnotion, for instance, is the efficacy of the benzodiazepines, baclofen,valproate, and gabapentin in the treatment of restless leg syndrome, animportant indication. See O'Keefe, Arch. Intern. Med. 156: 243-48(1996); Danek et al., in NEUROLOGICAL DISORDERS: COURSE AND TREATMENT,pages 819-23 (Academic Press 1996); Mellick & Mellick, Neurology45(suppl): 285-86 (1995). More generally, the present invention providesan effective therapy for restlessness syndromes with minimal sideeffects.

[0049] MOVEMENT DISORDERS: Various agents with known effects on theGABAergic system have been shown to decrease the dyskinetic movementcharacterizing movement disorders such as Parkinson's disease,Huntington's chorea, tardive dyskinesia, and stiff-man syndrome. Thisfact has highlighted a role for central GABAergic function in thecontrol and modulation of CNS excitability and movement. Lloyd &Morselli (1987), supra. A method of treatment according to the presentinvention that can effect an altered level of CNS activity, presumablyvia a GABAergic mechanism, will alleviate one or more symptoms of amovement disorder.

[0050] NEUROPROTECTION: Excitatory neurotransmitters such as glutamateand aspartate, as well as a variety of voltage-gated ion channels, arethought to play a central role in mediating cell death after a varietyof cerebral insults including, but not limited to, ischemia, trauma,seizure and hypoglycemia. Many studies have shown that compounds ortherapeutic strategies that decrease excitatory neurotransmission, forexample, glutamate antagonists, ion channel blockers, and the like,elicit a neuroprotective effect in animal models of cerebral insults.

[0051] Recent studies have shown that compounds such as GABAergic agents(chlormethiazole, valproate or muscimol) that enhance inhibitoryneurotransmission, also can elicit a neuroprotective effect followingthe same type of cerebral insults described above (Lyden, Chapter 10 in“Neuroprotective Agents and Cerebral Ischaemia”, IRN 40, Academic PressLimited, 1997). GABA and glycine are the primary inhibitoryneurotransmitters in the mammalian central nervous system and,therefore, it is expected that enhancement of inhibitoryneurotransmission via GABA or glycine agonists as well as via otheragents that have been shown to increase GABA or glycine inhibitoryneurotransmission (GABA/glycine reuptake inhibitors, GABA/glycinemetabolic inhibitors, GABA/glycine synthesis enhancers, GABA/glycinereceptor modulators, etc.) also will produce a neuroprotective effect.Studies have shown that the combination of the GABA agonist muscimol andthe glutamate antagonist, MK-801 appeared to confer an addedneuroprotective effect over either agent alone, although the effect wasmodest (Lyden, 1997).

[0052] Kindling has been proposed as a model to search for drugs withantiepileptogenic efficacy (Wada, Epilepsia 19: 217-227, (1974); Sato etal., Epilepsy Research 5: 117-124, (1990)); Silver et al., Ann. Neurol.29: 356-363, (1991)). The term “antiepileptogenic” refers to the idea ofinhibiting the processes that underly the development of epilepsy.“Anticonvulsant”, on the other hand, refers to the actual inhibition ofseizures in an epileptic model.

[0053] Various anticonvulsants that have been shown to delay theacquisition of seizures in animal models of kindling have been proposedto be antiepileptic versus anticonvulsant i.e., the compounds areneuroptotective and block the development of seizures rather than merelyblocking the seizure once the disorder is in place (Antiepileptic Drugs,Fourth Edition, Chapter 7., White, H. S. et al., Chapter 7, ExperimentalSelection, Quantification, and Evaluation of Antiepileptic Drugs(99-110) in Antiepileptic Drugs, Fourth Edition edited by R. H. Levy, R.H. Matson, and B. S. Meldrum, Raven Press Ltd., (1995)). Seizurekindling models are characterized by giving a sub-seizure elicitingelectrical or chemical stimulus (i.e., sub-threshold) over a period oftime (Goddard et al., Exp. Neurol. 25: 295-330, (1969)). The majority ofinitially non-convulsive animals that are exposed to such stimuli over anumber of days, eventually exhibit seizure activity to these stimuli,have a permanently lowered threshold, exhibit altered manifestations ofnormal behavior and, therefore, are considered “kindled.” The kindlingphenomenon has been proposed to underlie the development of disorderssuch as certain types of epilepsy syndromes. Several kindling models ofseizure development have been characterized.

[0054] Compounds that have been shown to delay or block acquisitions ofseizures in these kindling models have been suggested to be a possibleeffective therapy following cerebral insults including, but not limitedto, ischemia, haemorrhagic stoke, trauma, infection, seizure andhypoglycemia that can lead to an elevated incidence of seizure disorders(The Epilepsies: Etiologies and Prevention, 1999, Eds. Kotagal andLuders).

[0055] SUBSTANCE ABUSE/CRAVING: Anticonvulsants such as cambamazepine,that have shown efficacy in kindled models of epilepsy, have alsodemonstrated efficacy in reducing the symptoms of affective mooddisorders and substance abuse/craving in patients (Post, et al., Ann.N.Y. Acad. Sci. 537:292-308, (1988)); Post, et al., Epilepsia 25:234-239, (1984)); Post, et al., Psychopharmacology 72: 189-196, (1981))Halikas et al., 1989; Blumer et al., 1988). Post and Kopanda (1976) havedemonstrated a pharmacologic (chemical) kindling model employingsubconvulsive doses of cocaine as the stimulus. The progressive humanresponse to high cocaine usage such as irritability, restlessness,hypervigilance, and paranoia may be a human equivalent of the kindlingphenomenon observed in animals.

[0056] Several kindling models of seizure development have beencharacterized. Seizure kindling models are characterized byadministration of a sub-seizure eliciting electrical or chemicalstimulus (i.e., sub-threshold) over a period of time (Goddard et al.;1969). The majority of initially non-convulsive animals that are exposedto such stimuli over a number of days eventually exhibit seizureactivity to these stimuli, have a permanently lowered threshold, exhibitaltered manifestations of normal behavior and therefore are considered“kindled.” A kindling phenomenon has been proposed to underlie thedevelopment of disorders such as certain types of epilepsy syndromes,substance abuse/craving and affective mood disorders such as bipolar(Post et al. 1981, 1984, 1988, supra: Ballenger, et al., Br. J.Psychiatry 133: 1-14, (1978));

[0057] The pharmaceutical compositions of the invention displayanticonvulsant activity and efficacy in animal models of kindling and,accordingly, the inventive pharmaceutical compositions should be usefulin treating conditions associated with substance abuse/craving.

[0058] 3. Methods for Preparing Pharmaceutical Formulations

[0059] Identification of Active Compounds

[0060] The rhizomes and roots of Valeriana spp. (common name: valerian;family Valerianaceae) have been used for medicinal purposes sinceancient times. The most commonly used valerian preparations includeaqueous and hydroalcoholic extracts, such as tinctures, intended fororal administration. In addition, ammoniated valerian tinctures wereused medicinally in the English-speaking world since at least thebeginning of the seventeenth century. Hobbs, HerbalGram No. 21: 19-34(1989). In the last three decades, the sedative and antispasmodicproperties of valerian preparations have been attributed primarily tothe presence of chemically labile monoterpenoid iridoid triestercompounds called valepotriates (“valerian-epoxy-triesters(-ates)”).

[0061] The most common and abundant of the valepotriates, valtrate anddidrovaltrate, each contain two isovalerate moieties esterified to a“central” iridoid nucleus. Lin et al., Pharm. Res. 8: 1094-02 (1991).These acid- and heat-labile substances do not survive intact in thestomach following oral administration, but readily release two moles ofisovaleric acid for every mole of valepotriate. Furthermore, aqueousextracts of valerian rhizomes and roots retain their biologicalproperties, even though the valepotriate triesters are water-insoluble.Bos et al., Phytochem. Anal. 7: 143-51(1996).

[0062] The major, water-soluble, active principle of commonly usedvalerian extracts and other preparations, such as aqueous orhydroalcoholic extracts or tinctures, has been determined to be theester hydrolysis product, isovaleric acid. Ammonium isovalerate andisovaleramide are produced in ammoniated tinctures. Balandrin et al., J.Toxicol.-Toxin Rev. 14: 165 (1995). The structures of isovaleramide andrelated compounds are depicted in FIG. 1. In this way, the chemicallylabile valepotriates and other valerian-derivedmonoterpenoid-isovalerate esters, such as bornyl, lavandulyl, and ethylisovalerates, might be considered to act as “pro-drugs” and chemicalprecursors for isovaleric acid, its salts, and isovaleramide.

[0063] Isovaleramide has been isolated from valerian plants, mostprobably as an isolation artifact following treatment with ammonia.Buckova et al., Cesk. Farm. 26: 308 (1977); Chem. Abstr. 88: 86063z(1978); see also Bos et al. and Fuzzati et al., Phytochem. Anal. 7: 143,76 (1996). More recently, isovaleramide was shown to exhibit low acutetoxicity in vivo, no mutagenic potential, and clinically usefulanxiolytic properties (U.S. Pat. No. 5,506,268; PCT application WO94/28,888). Methods for preparing isovaleramide are well known.

[0064] Extracts of medicinal plants that are useful for treating thesymptoms of spasticity can be prepared by aqueous, hydroalcoholic, oralcoholic extraction, or by extraction with other suitable solventsusing methods well known to those skilled in the art. In the context ofthe present invention, useful extracts contain at least one of thefollowing: isovaleric acid, its salts or complexes, ethyl isovalerate,isovaleramide, N-ethyl isovaleramide, and their chemical precursors.Useful extracts also share the common property of releasing isovalericacid and/or isovaleramide upon hydrolysis in vivo. Standard methods forpreparing such extracts can be found in pre-1950 editions of the U.S.PHARMACOPOEIA (U.S.P.) and the NATIONAL FORMULARY (N.F.), as well as inwell-known references such as Gennaro (Ed.), REMINGTON'S PHARMACEUTICALSCIENCES, 18th ed. (Mack Publishing Co. 1990), Tyler et al.,PHARMACOGNOSY, 9th ed. (Lea and Febiger 1988), and Hare et al., THENATIONAL STANDARD DISPENSATORY (Lea Brothers 1905). Additional citationsappear in U.S. Pat. No. 5,506,268 and PCT application WO 94/28,888.

[0065] The principal historic sources of naturally occurring isovalericacid have been valerian rhizomes and roots, as well as those of closelyrelated plants in the family Valerianaceae. As discussed by Hobbs(1989), supra, these include the common valerian plant, Valerianaofficinalis L., as well as the East Indian valerian, V. wallichi DC.,and the biblical spikenard, Nardostachys jatamansi (Roxb.) DC. Inaddition to valerian rhizomes and roots, other plants which have beenused traditionally as sedative herbal medicines are known to contain, orto produce, isovaleric acid. These include hops (Humulus lupulus L.,family Moraceae, which is often used in herbal formulations incombination with valerian), “cramp bark” or “guelder rose” (Viburnumopulus L., family Caprifoliaceae), and “black haw” (V. prunifolium L.,root bark). Hare et al., THE NATIONAL STANDARD DISPENSATORY, pages 93,94, 159, 160, 169, 256, 642, 692-694, 766, 767, 932, 1031, 1383, 1384,1426, 1479, 1480, 1571, 1572, 1619, 1620, 1631-1633, 1661, and 1662 (LeaBrothers 1905); Heyl et al., J. Am. Chem. Soc. 42: 1744 (1920); Grier,Pharm. J. Pharm. 68: 302 (1929); Grier, Chem. Drug. (London) 110: 420(1929); Grieve, A MODERN HERBAL, pages 35-40, 265-276, 381, 382,411-415, 744-746, 781, 782, and 824-830 (Hafner 1959); Holbert, J. Am.Pharm. Assoc., Sci. Ed. 35: 315 (1946); Hoffmann, THE HERBAL HANDBOOK: AUSER'S GUIDE TO MEDICAL HERBALISM, pages 38, 39, 83 and 84 (Healing ArtsPress 1989).

[0066] As in the case of valerian rhizomes and roots, hops generateisovaleric acid from more chemically complex precursors upon oxidationor enzymatic breakdown. Millspaugh, AMERICAN MEDICINAL PLANTS, ANILLUSTRATED AND DESCRIPTIVE GUIDE TO THE AMERICAN PLANTS USED ASHOMEOPATHIC REMEDIES, pages 622-626 (Dover 1974); Hare et al., THENATIONAL STANDARD DISPENSATORY, pages 766-767 (Lea Brothers 1905);Grier, Chem. Drug. (London) 110: 420 (1929); Grieve, A MODERN HERBAL,pages 411-415 (Hafner 1959); Stevens, Chem. Rev. 67: 19 (1967); Duke,CRC HANDBOOK OF MEDICINAL HERBS, page 557 (CRC Press 1985).

[0067] Pharmaceutically acceptable salts of organic acids, such asisovaleric acid, which have been approved by the U.S. Food and DrugAdministration for commercial marketing include sodium, potassium,lithium, zinc, aluminum, calcium, and magnesium salts. REMINGTON'SPHARMACEUTICAL SCIENCES, 18th ed., page 1445 (Mack Publishing Co. 1990).Salts of isovaleric acid that are commercially available in the UnitedStates include the ammonium, sodium, potassium, and zinc isovalerates.

[0068] Pharmaceutically acceptable alcohols can form esters withisovaleric acid by methods that are well known in the art. See, forexample, March, ADVANCED ORGANIC CHEMISTRY: REACTIONS, MECHANISMS, ANDSTRUCTURE, fourth ed. (John Wiley and Sons 1992). Such alcohols maycontain more than one hydroxyl moiety, and are well tolerated in vivo.Examples of suitable alcohols include ethanol, certain carbohydrates andrelated compounds such as glucose, fructose, sucrose, xylose, andlactose, sugar alcohols such as dulcitol, mannitol, and sorbitol, sugaracids such as gluconic and glucuronic acids, glycerol, the polyolinositol, benzyl alcohol, certain phenols such as phenol, salicylicacid, saligenin, salicylamide, vanillin, p-hydroxycinnamic acid(p-coumaric acid), caffeic acid, ferulic acid, gallic acid, ellagicacid, quercetin, and eugenol. Other examples of suitable alcoholsinclude alkaloids and biogenic amines such as ephedrine,pseudoephedrine, phenylpropanolamine, tyramine, and dopamine, vitaminssuch as ascorbic acid (vitamin C), thiamine (vitamin B1), riboflavin(vitamin B2), pyridoxine (vitamin B6), cyanocobalamin (vitamin B12), thetocopherols (vitamin E), choline, folic acid, and pantothenic acid,monoterpenoid alcohols such as geraniol, nerol, and linalool, naturallyoccurring triterpenoid alcohols such as α- and β-amyrins, lupeol, andoleanolic and ursolic acids, bile acids such as cholic acid, deoxycholicacid, and taurocholic acid, and common naturally occurring plant sterols(phytosterols) such as β-sitosterol, stigmasterol, campesterol, andbrassicasterol. Tyler et al., PHARMACOGNOSY, 9th ed. (Lea and Febiger1988). Other such well-tolerated hydroxyl-containing compounds can bereadily identified by those skilled in the art, for example, byconsulting standard reference works such as THE MERCK INDEX andREMINGTON'S PHARMACEUTICAL SCIENCES, 18th ed. (Mack Publishing Co.1990). Esters of isovaleric acid that are commercially available in theUnited States include the bornyl, ethyl, n-butyl, isoamyl, and geranylisovalerates.

[0069] Isovaleric acid, ammonium isovalerate, and the esters ethylisovalerate, isoamyl isovalerate, 2-methylbutyl isovalerate, cinnamylisovalerate, methyl isovalerate, bornyl isovalerate, isobornylisovalerate, and menthyl isovalerate are approved by the FDA and arelisted in the Code of Federal Regulations as being acceptable flavoringagents which may be used in foods. 21 CFR §172.515 (1991). Valerian(Valeriana officinalis L.) rhizomes and roots and black haw (Viburnumprunifolium L.) bark are listed as acceptable natural flavoringsubstances and natural adjuvants in 21 CFR §172.510 (1991). Hops and“lupulin” are listed among substances that are generally recognized assafe (“GRAS”). 21 CFR §182.20 (1991).

[0070] Generally, esters of isovaleric acid are expected to behydrolyzed in vivo by ubiquitous esterase enzymes, thereby releasingisovaleric acid and the constituent alcohol. Particularly preferredamong the isovalerate esters are glyceryl mono-, di-, and especiallytri-isovalerates (“triisovalerin”), isovaleryl salicylic acid orsalicylate (salicylic acid isovalerate), ethyl isovalerate, andβ-sitosteryl isovalerate. See FIG. 1. Hydrolysis of these isovalerateesters in vivo releases isovaleric acid and glycerol (glycerin),salicylic acid (an analgesic, anti-inflammatory, and febrifuge), ethanol(ethyl alcohol or common “alcohol,” a CNS depressant), and β-sitosterol(a harmless phytosterol), respectively. With the exception of ethylisovalerate, these esters are non-volatile or only slightly volatile,thereby minimizing any unpleasant odors. Furthermore, in pure form theseesters possess the advantage of having neutral to pleasant odors, incontrast to the extremely unpleasant odors of isovaleric acid and itssalts, such as the ammonium, sodium, potassium, and zinc isovaleratesalts. Moreover, whereas ethyl isovalerate is a liquid, theglycerylmono-, di-, and tri-isovalerates, isovaleryl salicylate, andβ-sitosteryl isovalerate are expected to be solids at room temperature,thereby facilitating their formulation into various standard solid andliquid oral dosage forms well known in the art, such as tablets (e.g.,uncoated tablets, enteric-coated tablets, and film-coated tablets),capsules, gelcaps, powders, concentrates (drops), elixirs, tinctures,and syrups.

[0071] In addition to isovaleramide, various N-substituted amides ofisovaleric acid may be used in the inventive methods. These amides canbe prepared by methods well known in the art and may. See, for example,March, ADVANCED ORGANIC CHEMISTRY: REACTIONS, MECHANISMS, AND STRUCTURE,4th ed. (John Wiley and Sons 1992). Preferred amides include N-ethylisovaleramide, N-methyl isovaleramide, N, N-dimethyl isovaleramide,N-methyl,N-ethyl isovaleramide, N-(2-acetamido)isovaleramide(“N-isovaleryl glycinamide”), and N-isovaleryl GABA. See, for example,Tanaka et al., J. Biol. Chem. 242: 2966 (1967).

[0072] The present invention also is directed to compounds and methodsof using compounds that, by virtue of their structural similarity toisovaleramide, share similar pharmacological activities. These compoundsgenerally share the common structure:

[0073] Where

[0074] A=H, CH₃ or OH,

[0075] B=H, OH, or CH₃,

[0076] X=CH₂, CHCH₃, C(CH₃)₂, —O—, CH(OH)—, or —CH₂O—,

[0077] Y=—CO—, or —SO₂—, and

[0078] Z=H, CH₂CO₂H, or CH₂CONH₂

[0079] The structures of these compounds are shown in FIGS. 1a and 1 band include substituted isovaleramides such as 2-methylisovaleramide,3-methylisovaleramide, 2,2-dimethylisovaleramide,2,3-dimethylisovaleramide, 4-methylisovaleramide,2,4-dimethylisovaleramide, 3,4-dimethylisovaleramide,2,2,4-trimethylisovaleramide, 3-hydroxyisovaleramide,4-hydroxyisovaleramide, 4-hydroxy-3-methyl-isovaleramide,2-hydroxyisovaleramide, and 2,2-dimethyl-n-butyramide. For each of thesecompounds that contains one or more asymmetric centers, the presentinvention specifically includes each of the possible enantiomeric ordiastereomeric forms of the compound.

[0080] N,N-Diethyl isovaleramide (“Valyl”), although purported topossess CNS depressant (sedative) activity, recently has been shown topossess CNS stimulant (convulsant) properties; see U.S. Pat. No.5,506,268 and PCT application WO 94/28,888, supra. An amide ofisovaleric acid with p-aminophenol also can be prepared using standardmethods to provide a compound, “isovaleraminophen,” which is relatedstructurally to the drug acetaminophen (Tylenol®; see FIG. 1). In amanner analogous to that of the isovalerate esters, these substitutedamides should be hydrolyzed in vivo (in this case, via hepatic amidaseenzymes), releasing isovaleramide or isovaleric acid.

[0081] In addition to the amide compounds described above, the presentinvention also is directed to certain sulfonamide, sulfamate, andcarbamate compounds that, by virtue of their structural similarity toisovaleramide, share similar pharmacological activities. Preferredsulfonamides and sulfamates include 2-methyl-1-propylsulfonamide,1-methylethyl sulfamate, and 2-methyl-1-propyl sulfamate. Preferredcarbamates include isobutylcarbamate (CH₃)₂CHCH₂OCONH₂) andisopropylcarbamate (CH₃)₂CHOCONH₂).

[0082] Certain of the compounds and preparations discussed aboverepresent alternative forms for delivering isovaleric acid orisovaleramide in vivo. In cases such as isovaleryl salicylate and ethylisovalerate, the pharmacologically active moiety corresponding to thealcohol portion may be expected to exert its own pharmacologicaleffects. For example, compounds such as “isovaleraminophen” would beexpected to exhibit a “Tylenol®-like” effect, similar to acetaminophenas well as the effect expected from the isovaleric acid or isovaleramidemoiety. Such novel chemical combinations of a previously known,pharmacologically active alcohol, phenol, or primary or secondary aminewith isovaleric acid fall within the scope of the present invention.Similar chemical combinations with 2-methylisovaleric acid,3-methylisovaleric acid, 2,2-dimethylisovaleric acid,2,3-dimethylisovaleric acid, 4-methylisovaleric acid,2,4-dimethylisovaleric acid, 3,4-dimethylisovaleric acid,2,2,4-trimethylisovaleric acid, 3-hydroxyisovaleric acid,4-hydroxyisovaleric acid, 4-hydroxy-3-methyl-isovaleric acid,2-hydroxyisovaleric acid, and 2,2-dimethyl-n-butyric acid are within thescope of the present invention.

[0083] Preparation of Active Compounds

[0084] The compounds of the present invention may be prepared usingsynthetic methods that are well known in the art. For example, many ofthe carboxylic acid precursors of the amide compounds are commerciallyavailable, for example from the Aldrich Chemical Co., Milwaukee, Wis.,and can be converted into the corresponding amide by preparation of theacid chloride with thionyl chloride or oxalyl chloride, followed byreaction with ammonia or an amine. For compounds containing a hydroxylgroup distal to the carboxyl group, the hydroxyl group first isprotected using a suitable protecting group as described, for example,in Green, “Protective Groups in Organic Synthesis”, Wiley (1981), priorto preparation of the acid chloride. 2-hydroxy and 3-hydroxyisovaleramide are metabolites of isovaleramide in vivo, and can beisolated in high yield from the urine of a patient being treated withisovaleramide.

[0085] For compounds where the starting acid is not commerciallyavailable, the required acid can be prepared by straightforward methodsof organic synthesis known to the skilled chemist. For example,carboxylic acid esters may be deprotonated with a strongnon-nucleophilic base, such as lithium diisoropylamide, followed byalkylation with methyl iodide or methyl trifluoromethanesulfonate. Thealkylated ester is hydrolyzed and converted to the amide by the methodsdescribed above.

[0086] When the compounds contain one or more asymmetric centers, theindividual enantiomers may be prepared from optically active startingmaterials, or separated by traditional methods of resolution, such asfractional crystallization of salts with chiral amines, or bypreparation of amides with chiral amides, chromatographic separation,and hydrolysis of the amides. Alternatively, the amides can be preparedby well known methods of asymmetric synthesis, such as alkylation of anester or amide of the acid prepared using a chiral auxiliary. See, forexample, Evans et al, Tetrahedron, 44:5525 (1988) and Fadel et al.Asymmetry 1994:531.

[0087] Preparation of Pharmaceutical Compositions

[0088] The present invention also is directed to pharmaceuticalcompositions containing the active compounds described above. Thepharmaceutical compositions can contain a single active compound, or cancontain combinations of two or more of the active compounds. Thepharmaceutical formulations of the present invention can be preparedaccording to known methods to prepare pharmaceutically usefulcompositions, whereby active agents are combined in a mixture with apharmaceutically acceptable carrier. For instance, see REMINGTON'SPHARMACEUTICAL SCIENCES and GOODMAN AND GILMAN'S, both cited above. Acomposition is said to be in a “pharmaceutically acceptable carrier” ifits administration can be tolerated by a recipient patient. Sterilephosphate-buffered saline is one example of a pharmaceuticallyacceptable carrier. Other suitable carriers (e.g. saline and Ringer'ssolutions) are well known to those skilled in the art. See, for example,REMINGTON'S PHARMACEUTICAL SCIENCES, supra.

[0089] In general, the dosages of the antispasticity and anticonvulsantagents described herein will vary depending upon such factors as thepatient's age, weight, height, sex, general medical condition, andprevious medical history. For purposes of therapy, a compound of thepresent invention and a pharmaceutically acceptable carrier areadministered to a subject in need of such treatment in a therapeuticallyeffective amount.

[0090] The combination of active agent and carrier is said to beadministered in a “therapeutically effective amount” if the amountadministered is physiologically significant. An agent is physiologicallysignificant if its presence results in a detectable change in thephysiology of a recipient patient. In the present context, for example,an antispasticity agent is physiologically significant if the presenceof the agent results in the alleviation of one or more symptoms ofspasticity, while an anticonvulsant agent is physiologically significantif the presence of the agent results in the reduction of the severity,number, or duration of convulsions. Similarly, for each of thepathologies recited above, a compound is physiologically significant if,upon administration to a patient, it can alleviate or reduce aclinically recognized symptom of that pathology.

[0091] Isovaleramide and related compounds can be administered orallyusing solid oral dosage forms such as enteric-coated tablets, caplets,gelcaps, or capsules, or via liquid oral dosage forms such as syrups orelixirs. The indicated dosage of isovaleramide and related compounds asantispasticity agents is on the order of 50-1200 mg per dose or 1-20mg/kg body weight. Unit solid oral dosage forms preferably contain about50-800 mg per tablet or capsule, which typically would be taken 1-2 at atime for a maximum of four times per day, at a dosage of 1-20 mg/kg bodyweight. Liquid formulations can also be employed with active ingredientcompositions so as to provide 1-2 teaspoonfuls per dose. Furthermore,corresponding reduced dosage pediatric chewable and liquid oral dosageforms also can be administered. These compounds also can be added tofoods and beverages in the form of drops (with a dropper from a“concentrate” preparation) for oral administration. In addition,compounds such as isovaleramide may be formulated into chewing gum tofacilitate oral delivery and absorption.

[0092] Alternatively, isovaleramide and related compounds can beadministered by injection or other systemic routes, such as IV,transdermal or transmucosal administration, for example, nasally,buccally, or rectally, via suppositories. Oral administration is muchmore convenient, however, and therefore is preferred. For use in an oralanticonvulsant composition, the dosage level of active ingredient(s) ison the order of 50-1200 mg per dose or 1-20 mg/kg body weight.

[0093] In addition to a use in humans, isovaleramide and relatedcompounds can be used, for example, as antispasticity agents oranticonvulsant agents, in animals such as cats, dogs, birds, horses,cattle, mink, poultry, and fish. In such cases the active compound maybe administered by injection or other systemic routes, such astransdermal or transmucosal administration (for example, rectaladministration via suppositories), or orally by addition to food ordrink. As an antispasticity agent, the indicated oral dosage ofisovaleramide and/or related compounds per kilogram of body weight ofsuch animals is about 50-1200 mg/kg, depending upon the species ofanimal and the route of administration.

[0094] The indicated oral dosage of isovaleramide and/or relatedcompounds per kilogram body weight as anticonvulsant agents for animalsis in the range of about 50-1200 mg/kg, depending upon the species ofanimal and the route of administration.

[0095] The present invention thus contemplates a variety ofpharmaceutical compositions containing the active compounds describedabove (including isovaleramide, isovaleric acid, and/or itspharmaceutically acceptable salts, substituted amides, alcohol esters,sulfonamide, sulfamate, and carbamate analogs) as active ingredientsthat are suitable for oral, IV, parenteral, transdermal, transmucosal,intranasal, buccal, or rectal administration. Although such compoundsmay be present as incidental by-products in certain pharmaceuticalformulations which are outside the scope of the present invention, thecommon feature of the present formulations is that isovaleramide,isovaleric acid, and/or its pharmaceutically acceptable salts,substituted amides, alcohol esters, and sulfonate, sulfamate, andcarbamate analogs, are present in a standardized amount. That is, thepharmaceutical formulations contain a predetermined, chemically defined,and quantifiable amount of at least one of such compounds to enable thedetermination of the quantity of a particular composition required toachieve the dosage levels described herein.

[0096] It is further understood that isovaleramide and/or relatedcompounds can be used in combination with other pharmaceutically activeingredients.

[0097] 4. Demonstrating Therapy-Implicating Activity

[0098] The suitability and effectiveness of a given pharmaceuticalformulation for the alleviation of a pathology, as discussed above, canbe demonstrated using animal models such as (but not limited to) thosedescribed below.

[0099] (a) The Mutant Spastic Mouse

[0100] The mutant spastic mouse is a homozygous mouse that carries anautosomal recessive trait of genetic spasticity. The mouse is normal atbirth, and then the mouse develops a coarse tremor, abnormal gait,skeletal muscle rigidity, and abnormal righting reflexes at two to threeweeks of age. No structural abnormalities have been found. Rather, themouse has a deficit of glycine receptors throughout the central nervoussystem. Drugs that either potentiate the binding or synthesis of GABA,such as valproate and the benzodiazepines, are effective compounds toameliorate some of the symptoms of spasticity in this model, as well asin humans.

[0101] The assessment of spasticity in the mutant spastic mouse can beperformed by electrophysiological assessment similar to the EMGrecordings described below. One can also, on a more crude scale, measurerighting. These mice have an abnormal delayed righting reflex whenplaced on their backs. Any righting reflex over one second is consideredabnormal. Most normal mice cannot even be placed on their backs. Tremorcan be evaluated by holding mice by their tails and rating the tremorsubjectively by “absent,” “slight,” “moderate,” or “severe.” Flexibilityis assessed by placing the mouse on a glass object with smoothly roundedgrooves and rims. The glass object is lifted about 12 inches above thetable and slowly tilted until almost vertical. Normal mice will climbabout the object for a minute or more before falling to their feet.Spastic mice usually remain stiffly in one position and soon fall ontotheir backs. Chai et al., Proc. Soc. Exptl. Biol. Med. 109: 491 (1962).

[0102] (b) The Acute/Chronic Spinally Transected Rat and the AcuteDecerebrate Rat

[0103] There are several models of spasticity including the acutedecerebrate rat, the acute or chronic spinally transected rat, and thechronically spinal cord-lesioned rat. (Wright, J., et al., Clin Orthop253:12, 1990). The acute models, although of proven value in elucidatingthe mechanisms involved in the development of spasticity, have comeunder criticism due to the fact that they are acute. The animals usuallydie or have total recovery from spasticity. The spasticity developsimmediately upon intervention, unlike the spasticity that evolves in thehuman condition of spasticity, which most often initially manifestsitself as a flaccid paralysis. Only after weeks and months doesspasticity develop in humans. Some of the more chronic-lesioned orspinally transected models of spasticity do postoperatively show flaccidparalysis. At approximately four weeks post-lesion/transection, theflaccidity changes to spasticity of variable severity. Although all ofthese models have their own particular disadvantages and lack of truerepresentation of the human spastic condition, they have provided muchinformation about the nature of spasticity. These models have alsoprovided methods to test various treatment paradigms that have led tosimilar treatments being tested in humans. Many of these models havealso made use of different species, such as cats, dogs, and primates.Baclofen, diazepam, and tizanidine, effective antispastic agents inhumans, are effective on different parameters of electrophysiologicassessment of muscle tone in these models.

[0104] (c) Primary Observation Irwin Test in the Rat

[0105] This method is based on that described by Irwin,Psychopharmacologia 13: 222-57 (1968). It is used to detectphysiological, behavioral, and toxic effects of a test substance, andindicates a range of dosages that can be used for later experiments.Typically, rats (three per group) are administered the test substanceand are then observed in comparison with a control group given vehicle.Behavioral modifications, symptoms of neurotoxicity, pupil diameter, andrectal temperature are recorded according to a standardized observationgrid derived from that of Irwin. The grid contains the following items:mortality, sedation, excitation, aggressiveness, Straub tail; writhes,convulsions, tremor, exophthalmos, salivation, lacrimation,piloerection, defecation, fear, traction, reactivity to touch, loss ofrighting reflexes, sleep, motor incoordination, muscle tone,stereotypies, head-weaving, catalepsy, grasping, ptosis, respiration,corneal reflex, analgesia, abnormal gait, forepaw treading, loss ofbalance, head twitches, rectal temperature, and pupil diameter.Observations are performed at 15, 30, 60, 120, and 180 minutes followingadministration of the test substance, and also 24 hours later. The testsubstance can be administered intraperitoneally (i.p.) subcutaneously(s.c.) or orally (p.o.).

[0106] (d) Rotarod Test in the Rat and Mouse

[0107] This is a test of neurological deficits using the methoddescribed by Dunham et al., J. Am. Pharm. Assoc. 46: 208-09 (1957). Ratsor mice are placed on a rod rotating at a speed of eight turns perminute. The number of animals which drop off the rod before threeminutes is counted and the drop-off times are recorded (maximum: 180sec). Ten rats are studied per group and the test is performed blind.The test compound is administered i.p. 60 min prior to testing.Diazepam, a benzodiazepine, is administered at 8 mg/kg, i.p., as thereference substance. A control group administered the vehicle is alsoincluded in the study.

[0108] (e) Anticonvulsant Activity

[0109] There are numerous in vivo models involving different kinds ofseizures and behavioral effects that are relevant for clinicallydistinct forms of epilepsy. It therefore is prudent to test for effectsin several models, because it may be an oversimplification to supposethat the same mechanism underlies all forms of seizure activity.

[0110] One useful model is provided by the Frings audiogenicseizure-susceptible mouse, a model of reflex epilepsy. At the time oftesting, individual mice are placed into a round Plexiglas chamber andexposed to a sound stimulus of 110 decibels, 11 kHz, for 20 seconds.Animals not displaying tonic hindlimb extensions were consideredprotected. In addition, the seizure score for each mouse can be recordedas: (1) running for less than 10 seconds; (2) running for greater than10 seconds; (3) clonic activity of limbs and/or vibrissae; (4) forelimbextension/hindlimb flexion; and (5) hindlimb extension.

[0111] The average seizure score can be calculated for each group ofmice employed in the dose-response study. At each dose, mice are alsotested on a rotarod for testing of motor impairment (toxicity). Testingfor motor impairment on the rotarod involves placing a mouse for athree-minute trial period on a one-inch diameter rod rotating at sixrevolutions per minute. If the mouse falls off of the rotating rod threetimes within the three-minute time period, it is considered a toxicresponse.

[0112] (f) Anti-Manic Activity

[0113] The amphetamine-induced hyperactivity model in rats can be usedto assess the possible use of compounds in the treatment of affectivemood disorders. In addition to being a test for classical and a typicalantipsychotic activity, this procedure has also been proposed as asimple animal model of manic behavior. Costall et al., Brain Res. 123:89-111 (1977).

[0114] Anticonvulsants, such as cambamazepine, that have shown efficacyin kindled models of epilepsy, have also demonstrated efficacy inreducing the symptoms of affective mood disorders and substanceabuse/craving in patients (Post, J. Clin. Psychiatry 50: 45-47, (1989),Halikas, et al., Lancet 18: 623-624, (1989); Blumer et al., Compr.Psychiatry 29: 108-122, (1988)).

[0115] (g) Neurogenic Inflammation of the Meninges

[0116] Neurogenic inflammation within the meninges has been proposed asan event in the underlying pathology of migraine headaches. Lee et al.,Brit. J. Pharmacol. 116: 1661-67 (1995). Compounds are tested for theirability to block the leakage of radiolabeled bovine serum albumin withinthe dura mater post trigeminal stimulation.

[0117] (h) Analgesic Properties

[0118] There are many whole-animal assays for determining analgesicproperties, such as writhing, hotplate, tail flick, arthritic pain, pawpressure tests, and the Bennet or Chung models of neuropathic pain.Albe-Fessard et al., in 13 ADVANCES IN PAIN RESEARCH AND THERAPY, pages11-27 (Raven Press 1990).

[0119] (i) Movement Disorders and Restlessness Syndromes

[0120] Animal models exist for the study of movement disorders andrestlessness syndromes, for example, drug-induced akathisias, serotoninsyndrome, rotation induced by unilateral nigral lesions. Lloyd &Morselli (1987), supra. Additionally, individual case reports ofanecdotal efficacy of compounds in humans have been a source for supportfor these indications. Mellick & Mellick (1995), supra; Olson et al.,Am. J. Med. 102: 60-66 (1997).

[0121] (j) Neuroprotection

[0122] Kindling has been proposed as a model that can be used toidentify drugs with antiepileptogenic efficacy (Wada, 1974; Sato et al.,1990; Silver et al., 1991). The term “antiepileptogenic” refers to theidea of inhibiting the processes that underly the development ofepilepsy thereby providing a “neuroprotective” effect. “Anticonvulsant,”on the other hand, refers to the acutal inhibition of seizures in anepileptic model. Several models of kindling are useful. Theamygdala-kindled rat is such a model (Tober, C., Eur. J. Pharmacol. 15:163-169, (1996)). Seizure kindling models are characterized by giving asub-seizure eliciting electrical or chemical stimulus (i.e.,sub-threshold) over a period of time (Goddard et al.; 1969). Themajority of initially non-convulsive animals that are exposed to suchstimuli over a number of days, eventually exhibit seizure activity tothese stimuli, have a permanently lowered threshold, exhibit alteredmanifestations of normal behavior and therefore are considered“kindled.”

[0123] Acute cerebral insults such as status epilepticus, traumaticinjury and stroke induce damage to selective neuronal populations in thehippocampus (Matsuyama, et al., J. Cereb. Blood Flow Metab. 13: 229-234,(1993)); Sloviter, Science 235: 73-76, (1987)) suggesting thatsubstances designed to prevent the neuronal damage that occurs in avariety of human neurological diseases would be therapeutically useful.Jolkkonen, et al., Neuroreport 7: 2031-2035, (1996) found thataugmentation of GABAergic inhibition by chronic infusion of the GABAtransaminase inhibitor, vigabatrin, prevented the delayedseizure-induced damage following kainate-induced status epilepticus.

[0124] Stroke in humans is a highly variable clinical condition,dependent upon pre-existing disease in a patient, the site and severityof the stroke, the type of stroke (ischemic or hemorrhagic), and thetime from onset to presentation for treatment. A number of animal modelsof stroke have been developed over the past several years to aid in ourunderstanding of the pathophysiological mechanisms of neuronal injuryand to allow for the evaluation of potential neuroprotective agents(Ginsberg et al., Stroke 20: 1627-1642, 1989; Hunter et al, Trends.Pharmacol. Sci. 16: 123-128, 1996). A major goal of these animal modelshas been to reduce the biological variability, by controlling oreliminating the variables mentioned above, to facilitate data analysisand interpretation. In doing so, however, these animal models do notperfectly mimic the human condition.

[0125] (k) Substance Abuse/Craving

[0126] Kindling phenomenon has been proposed to underlie the developmentof disorders such as epilepsy substance abuse/craving and affective mooddisorders such as bipolar (Post et al. 1981: Post et al., 1984;Ballenger et al., 1978; Post et al., 1988). Anticonvulsants, such ascambamazepine, that have shown efficacy in kindled models of epilepsy,have also demonstrated efficacy in reducing the symptoms of affectivemood disorders and substance abuse/craving in patients (Post and Weiss,1989, Halikas et al., 1989; Blumer et al., 1988). Post et al., (Biol.Psychiatry 11: 403-419, (1976)) have demonstrated a pharmacologic(chemical) kindling model employing subconvulsive doses of cocaine asthe stimulus. The progressive human response to high cocaine usage suchas irritability, restlessness, hypervigilance, and paranoia may be ahuman equivalent of the kindling phenomenon observed in animals.Recently, the anticonvulsant drug, vigabatrin, was proposed as apossible treatment for cocaine or nicotine craving (Dewey, et al.,Synapse 31:76, (1999)).

[0127] The therapeutic effects of isovaleramide, isovaleric acid, andrelated compounds in various of the assays described above, combinedwith a general lack of toxicity, make the compounds of the presentinvention ideal agents for the treatment of the pathologies describedabove, including spasticity and convulsions/seizures. With thisbackground, the present invention will be understood more readily byreference to the following examples, which are provided for purposes ofillustration and are not intended to be limiting of the invention.

EXAMPLE 1 Use of a Valerian Preparation to Alleviate Symptoms ofSpasticity Associated with Multiple Sclerosis

[0128] A human female subject, age 42, suffering from one or moresymptoms of multiple sclerosis, was experiencing a considerable amountof stress and was experiencing difficulty in getting to sleep anddelayed onset of sleep at night. The sleep that did occur was disturbedby stressful dreams and frequent awakening as well. The subject alsoexperienced frequent nighttime painful extensor spasms of the lowerextremities that would often awaken the subject from her sleep. Thefollowing day, these painful extensor spasms resulted in a deep musclepain (bruising sensation), with muscle/joint stiffness.

[0129] The subject decided to consume a preparation of valerian that wasnoted for its sleep-aid properties. The valerian product, “Baldriparanstark N,” consists of tablets manufactured in Germany that containextracts of valerian root, hops, and lemon balm. The coated, pressedtablets each contain 95 milligrams of a dried 70% (v/v) ethanol extractof valerian root, 15 milligrams of a dried 45% (m/m) methanol extract ofhops, and 85 milligrams of a dried water extract of lemon balm.Surprisingly, the valerian preparation not only facilitated the onset ofsleep and improved the quality of sleep for the subject, but it was alsonoticed that the painful extensor spasms were alleviated. The subjectnoted that upon awakening during the night to use the bathroom, she didnot experience the painful extensor spasms upon getting out of bed northe usual stiff-leg sensation. The subject continues to consume the samevalerian product for the alleviation of these symptoms on an as-neededbasis (pn or pro re nata) and continues to experience relief.

EXAMPLE 2 Use of a Valerian Preparation to Alleviate Symptoms ofSpasticity Associated with Spinal Cord Injury

[0130] A human male subject, age 38, suffers symptoms of spasticity(hyperreflexia, tendon jerks, and extensor spasms) that evolved from anearlier injury to the spinal cord. All of these symptoms interrupt anddecrease the quality of sleep experienced by this individual. Upontaking the same German-made preparation of valerian described in Example1, the subject noted considerable improvement in the quality of sleep aswell as a significant reduction in night-time extensor spasms. Thissubject continues to consume the preparation on an as-needed (prn) basisfor the alleviation of the symptoms described above.

EXAMPLE 3 Isovaleramide Antispasticity Tests

[0131] (1) Assessment of Spasticity in Chronic Spinally Transected Rats

[0132] In these studies, male albino Holtzman-derived rats (HarlanSprague-Dawley Laboratories) weighing 270-530 grams were used assubjects. The animals were housed independently and had continuousaccess to food and water throughout the experiments.

[0133] All procedures were reviewed and approved by the InstitutionalAnimal Care and Use Committee. Animals were anesthetized using a mixtureof isoflurane and oxygen at a flow rate of 4 liters/minute.

[0134] The rats were then placed in a stereotaxic frame and anesthesiawas maintained. An incision was made so that the paraspinal musclescould be retracted and a laminectomy performed between T6-T9. A one- totwo-millimeter portion of the spinal cord was removed by evacuation andreplaced with Gel foam to reduce bleeding, after which the incision wasclosed in layers.

[0135] Following the transection, rats were placed in a room in whichthe ambient temperature was raised to about 80° F. with a space heaterto maintain body temperature. On the following morning post-surgery, thehindquarters of the spinalized rats were bathed and their urineexpressed manually by applying pressure to their bladders. Experimentswere conducted between 21 and 28 days after surgery. For the first twoweeks, these rats were given 0.25 ml of the antibiotic SulfatrimPediatric Suspension orally to prevent bladder infection.

[0136] A commercial antibiotic cream was applied to any part of the skinthat showed signs of decubitus lesions. Within approximately two weeks,all animals regained bladder control and were no longer given antibiotictreatment. Advokat, Brain Res. 684: 8 (1995). Assessment of spasticitywas performed before and after drug treatment such that each animalserved as its own control.

[0137] Initial assessment of spasticity was performed by the subjectivescoring method of rating the resulting spasticity response elicited withan innocuous stimulus, i.e., a metal probe, that was pressed against thelower abdomen at four specific sites. The spastic reaction was evaluatedfor each of the four trials using a scale ranging from zero (no spasticresponse in all four trials) to four (a maximum, tonic-clonic reactionelicited in all four trials). All spasticity scores, pre- andpost-treatment, were transformed to indicate the percent spasticity suchthat a score of 0/4=0%, 1/4=25%, etc. These raw or normalized scoreswere analyzed with a one-way repeated measures ANOVA.

[0138] As shown in FIG. 2, isovaleramide at a dose of 300 mg/kg, i.p.,was efficacious at 15, 30, 60, and 120 minutes post-administration inreducing the spasticity scores (45-65%). By the next day, i.e., by 1440minutes (24 hours), the spasticity scores had essentially returned tobaseline values. No overt behavioral toxicity or motor impairment wasobserved at this dose. The rats were alert and able to grasp with theirnon-paralyzed front paws as were the control, untreated rats.

[0139] With reference to FIG. 3, the polysynaptic flexor-reflexresponses, to test stimuli which activate high-threshold afferents, wererecorded as EMG activity from the ipsilateral hamstring muscle.Supramaximal electric shocks were applied to the hindpaw, and recordingelectrodes were placed in the biceps femoris semitendinosus muscle. Fivesets of stimuli were made at each time point. The flexor reflex wasrecorded, in both the pre-drug and the post-drug periods, every 30minutes once a stable baseline response was achieved. See Hao et al.,Eur. J. Pharmacol. 191: 407 (1990).

[0140] Thus, the responses were determined in spinalized rats byobserving the flexor-reflex response (FIG. 3) before treatment and ateach of 30, 60, 90, and 120 minutes following administration ofisovaleramide (300 mg/kg p.o.), baclofen (10 mg/kg s.c.) and vehicle(water, 12 ml/kg p.o.), respectively.

[0141] Isovaleramide was shown to reduce the magnitude of theflexor-reflex responses, at all time points in a chronic spinalized ratwith similar efficacy to baclofen, the positive control.

[0142] In FIG. 4, the responses from FIG. 3 and additional doses ofisovaleramide and baclofen are converted to a total-area-under-the-curveformat, covering the entire, two-hour measurement period. Alldrug-treated groups differed significantly from vehicle (p<0.05), basedon a one-way analysis of variance. Between the drug-treated groups, nodifferences were found in total reduction of the flexor reflex over thetwo-hour period (pairwise multiple comparison, Student-Newman-Keulsmethod).

[0143] (2) Primary Observation Irwin Test in the Rat

[0144] Administered i.p. in the rat, isovaleramide induced no changesfrom saline-injected controls at doses up to 256 mg/kg. At 512 mg/kg,slight sedation from 60 to 120 minutes, loss of traction (observed inonly one of three rats) at 120 minutes, and decreased muscle tone from60 to 120 minutes were observed. At 1024 mg/kg, marked sedation up to 30minutes was observed, becoming moderate up to 120 minutes, then slightat 180 minutes. Decreased fear also was observed at this dose up to 30minutes and in one of three rats up to 120 minutes. Decreased reactivityto touch up to 120 minutes, decreased muscle tone up to 180 minutes,slight hypothermia up to 120 minutes, and an abnormal gait (rolling)from 60 to 80 minutes were also observed at this dose. Loss of graspingand loss of righting reflex occurred, in one of three rats, at 15minutes at this dose.

[0145] (3) Rotarod Test in the Rat and the Frings Mouse

[0146] Isovaleramide, administered at doses of 128, 256, and 512 mg/kg(i.p.) 60 minutes before a test on the rotarod, did not significantlyaffect rotarod performance in the rat. See Table 1. In contrast,diazepam dose-dependently decreased rotarod performance. TABLE 1 Effectsof Isovaleramide and Diazepam in the Rotarod Test in the Rat Dose of:Number^(b) Drop-Off Time (sec) Isovaleramide of Rats Mean ± % changefrom (mg/kg)^(a) Falling S.E.M. t value control 0 5 135.5 ± 18.0  — —128 6 134.5 ± 20.7^(c) 0.036  −1% 256 7  98.4 ± 23.3^(c) 1.261 −27% 5127 115.9 ± 20.5^(c) 0.717 −14% Diazepam (mg/kg)^(a) 4 9 55.8 ± 20.6^(d)2.909 −59% 8 10 + ^(e) 16.3 ± ^(f   ) 6.222 −88%

[0147] Isovaleramide, administered at doses up to 512 mg/kg (i.p.) 15minutes before a test on the rotarod in the Frings mouse, did not affectperformance significantly. In contrast, doses of 300 mg/kg, 600 mg/kg,and 1000 mg/kg (i.p.) decreased rotarod performance in 1/8, 4/8, and 8/8of Frings mice tested, respectively.

EXAMPLE 4 Anticonvulsant Activity in the Frings AudiogenicSeizure-Susceptible Mouse Model of Epilepsy

[0148] The results of Table 2 demonstrate the anticonvulsant activity ofisovaleramide when administered i.p. in this animal model of epilepsy.Isovaleramide also displayed a quick onset and a relatively shortduration of action. Anticonvulsant activity was noted as early as 15minutes, but decreased substantially by two hours. All quantitativestudies therefore were conducted at 15 minutes. At this time point, themedian effective dose (ED₅₀) for protection against tonic extension was126 mg/kg, i.p. In addition, a dose-dependent reduction in seizure scorewas observed at this time point. At doses markedly higher than thoseproviding anticonvulsant activity (>300 mg/kg), animals treated withisovaleramide displayed behavioral toxicity that was characterized bytheir inability to maintain their balance on the rotarod. No notabletoxicity was observed at doses less than 300 mg/kg. The median toxicdose (TD₅₀) for rotarod impairment was 531 mg/kg, i.p. Thus, thecalculated protective index (TD₅₀/ED₅₀) was about 4.2.

[0149] Therefore, despite the relatively low potency of isovaleramide inthis model, it still displayed a relatively good separation betweenactivity and toxicity. Isovaleramide thus had a surprising andunexpected efficacy, based on existing structure-activity relationshipsfor amides and their corresponding acids, as an anticonvulsant in theFrings audiogenic seizure-susceptible mouse model of reflex epilepsy.The activity profile of isovaleramide is similar to that of thebroad-spectrum anticonvulsant, sodium valproate. Compounds similar instructure to valproate as well as isovaleric acid have been shown inprevious literature to elevate GABA levels throughout the CNS. It isthis function, primarily, that the anticonvulsant activity of valproateis attributed to, although other mechanisms have been suggested.Isovaleric acid, on the other hand, was reported in the literature to beinactive as an anticonvulsant, although it was reported to elicit aslight increase in GABA levels in the brains of mice. For example, seeLöscher et al., Neuropharmacology 24: 427 (1985); Keane et al., loc.cit. 22: 875 (1983); Keane et al., Pharmacol. Res. Commun. 17: 547(1985). TABLE 2 Effect of Isovaleramide on the Audiogenic SeizureSusceptibility of Frings Mice Following Intraperitoneal AdministrationNumber^(a) Number^(a) Dose of Seizure Protected Showing IsovaleramideScore ± of Eight Mice Toxicity of Eight (mg/kg, i.p.) S.E.M. Tested MiceTested 75 4.4 ± 0.6 1 0 112.5 4.0 ± 0.6 2 0 150 2.0 ± 0.6 6 0 300 1.0 ±0   8 1 600 — 4 1000 — 8 ED₅₀ for protection: 126 mg/kg (98.8 -168^(b))TD₅₀: 531 mg/kg (372 -711^(b))

[0150] The results of Table 3 demonstrate that isovaleramide displayedanticonvulsant activity when administered orally in this animal model ofepilepsy. TABLE 3 Effect of Isovaleramide on the Audiogenic SeizureSusceptibility of Frings Mice Following Oral Administration Number^(c)Number^(a) Showing Protected Toxicity Dose of Seizure of Eight of EightED₅₀ for Compound Score ± Mice Mice protection TD₅₀ (mg/kg) S.E.M.Tested Tested (mg/kg) (mg/kg) 100 4.5 ± 0.5 1 — — 200 2.9 ± 0.8 4 — —300 1.4 ± 0.5 7 1 186 600 0.25 ± 0.25 8 1 (122- 1009 255)^(e) 1000 — — 5(677- 1321)^(e) 1500 0.6 ± 0.2  8^(b) 5 2000 0 ± 0   7^(b,d)  7^(d)

[0151] The results of Table 4 and Table 5 demonstrate that theisovaleramide analogs N-(2-acetamido)isovaleramide and2-methylisovaleramide displayed anticonvulsant activity whenadministered orally in this animal model of epilepsy. TABLE 4 Effect ofN-(2-acetamido) isovaleramide on the Audiogenic Seizure Susceptibilityof Frings Mice Following Oral Administration Dose of Number^(a)Number^(a) N-(2-ace- Number^(a) Number^(a) Showing Showing tamido)Protected Protected Toxicity of Toxicity of Isovaler- of Four Mice ofFour Mice Four Mice Four Mice amide Tested at 30 Tested at 120 Tested at30 Tested at 120 (mg/kg) minutes minutes minutes minutes 30 0 0 0 0 1000 0 0 0 300 0 0 0 0 1000 3 4 1 0

[0152] TABLE 5 Effect of 2-methylisovaleramide on the Audiogenic SeizureSuscepti- bility of Frings Mice Following Oral Administration Number^(a)Number^(a) Dose of Number^(a) Number^(a) Showing Showing 2-methylProtected Protected Toxicity of Toxicity of isovaler- of Four Mice ofFour Mice Eight Mice Eight Mice amide Tested at 30 Tested at 120 Testedat 30 Tested at 120 (mg/kg) minutes minutes minutes minutes 30 0 0 0 0100 1 0 0 0 300 4 1 2^(a) 0

[0153] In general, the historical literature on the structure-activityrelationships of anticonvulsant activity around compounds similar tovalproate have taught away from simple, unsubstituted compounds such asisovaleramide. It is thus a surprising and unexpected observation thatisovaleramide has demonstrated an efficacy profile similar to that ofvalproate in the Frings audiogenic seizure-susceptible mouse model and asimilar separation of activity between efficacy and toxicity as measuredby rotarod performance. These observations indicate that isovaleramideis an effective therapeutic agent as a broad-spectrum anticonvulsant.Isovaleramide is known for its relative lack of toxicity in mutagenicityand cytotoxicity tests. See U.S. Pat. No. 5,506,268 and PCT applicationWO 94/28,888. On the other hand, valproate has long been noted for itshepatotoxicity-causing profile. For example, see Löscher et al.,Neuropharmacology 24: 427 (1985).

EXAMPLE 5 Anticonvulsant Activity in the Amygdala-Kindled Rat

[0154] Isovaleramide was evaluated for its ability to block theexpression of amygdala-kindled seizures in fully kindled rats.Isovaleramide was evaluated for its ability to block the kindled motorseizure (seizure scores of 4 and 5) and limbic behavioral seizures(seizure score between 1-3) as well as to affect changes inafterdischarge duration.

[0155] Adult, male Sprague-Dawley rats weighing at least 230 gr wereimplanted with a teflon-coated bipolar electrode sterotaxically placedin the anterior basolateral nucleus of the amygdala under ketamine andxylazine anesthesia. The electrode was implanted at the followingcoordinates with Bregma as zero: AP-2.2 mm, ML-4.7 mm, DV-8.7 mm. Aftera one-week recovery period, animals were kindled to Stage 5 behavioralseizures using a stimulus consisting of a 50 Hz, 1 sec train of 1 msbiphasic 150 uA pulses that were delivered once daily until 10consecutive stage 5 seizures were evoked. Testing of isovaleramide wasinitiated after a one-week, stimulus-free period. On the compound testday, rats displaying a stage 5 seizure were divided into multipletreatment groups (i.e. vehicle control and isovaleramide treatment).Sixty minutes after oral dosing, individual rats received a 300 uA, 1sec duration stimulation and their seizure score and afterdischargeduration recorded. Seizure score was classified according to Racine(Electroencephalogr. Clin. Neurophysiol. 32:281-294, (1972): stage 0: noabnormal behavior; stage 1: mouth or facial movements; stage 2: mouth orfacial movements and head nodding; stage 3: stage 2 and forelimb clonus;stage 4: stage 3 and rearing; stage 5: stage 4 and falling. A score of2-3 represents a focal seizure while a score of 4-5 representssecondarily generalized seizures. Afterdischarge duration was the totalduration of the amygdala electroencephalogram spikes with an amplitudeof at least twice the amplitude of the prestimulus recording and afrequency greater than 1/sec.

[0156] Isovaleramide was effective in reducing in a dose-dependentmanner the generalized seizure responses of fully kindled rats.Isovaleramide decreased the mean seizure score and the afterdischargeduration showing that it exerts anticonvulsant activity against bothfocal (seizure score 1-3) and secondarily generalized seizures (seizurescore 4-5).

EXAMPLE 6 Antiepileptogenic Effect in the Amygdala-Kindled Rat

[0157] In these studies, groups of adult, male Sprague-Dawley ratsweighing at least 230 gr were implanted with a teflon-coated bipolarelectrode sterotaxically placed in the anterior basolateral nucleus ofthe amygdala under ketarine and xylazine anesthesia. The electrode wasimplanted at the following coordinates with Bregma as zero: AP-2.2 mm,ML-4.7 mm, DV-8.7 mm. Chronic treatment with vehicle (0.5%carboxymethylcellulose, p.o.) or isovaleramide (500 mg/kg, p.o., 0.08ml/gr of body weight) was initiated after a seven-day postoperativerecovery period. After a 30 min pretreatment period, animals werestimulated at a suprathreshold current of 300 uA for 1 second daily(i.e, except weekends) until all control animals exhibited 7 consecutivestage 5 seizures (Racine, 1972). After 11 treatment days, all animalswere permitted a 7-day drug- and stimulus-free period. Animals were thenchallenged with 300 uA once daily starting at day 18 until all animalsdisplayed 5 consecutive stage 5 seizures. Seizure score andafterdischarge duration were recorded after each stimulation. Seizurescore was classified according to Racine scale (1972): stage 0, noabnormal behavior; stage 1, mouth or facial movements; stage 2, mouth orfacial movements and head nodding; stage 3, stage 2 and forelimb clonus;stage 4, stage 3 and rearing; stage 5, stage 4 and falling. A score of2-3 represents a focal seizure while a score of 4-5 representssecondarily generalized seizures. Afterdischarge duration was the totalduration of the amygdala electroencephalogram spikes with an amplitudeof at least twice the amplitude of the prestimulus recording and afrequency greater than 1/sec. The results demonstrate theantiepiletogenic effect of a daily 500 mg/kg p.o. dose of isovaleramide,which delayed the increases in both seizure score and afterdischargeduration which normally develop during electrical kindling in theamygdala-kindled rat. Although isovaleramide at this dose elicited adelay in the acquisition of seizure development, over time, the ratseventually developed full stage 5 seizures. We have shown in the Fringsmouse that isovaleramide has a quick onset of action with a relativelyshort biological half-life. A greater antiepileptogenic effect may haveoccurred if the dosing schedule had been maximized for longer exposure.

[0158] Although the foregoing refers to particular preferredembodiments, it will be understood that the present invention is not solimited. It will occur to those of ordinary skill in the art thatvarious modifications may be made to the disclosed embodiments and thatsuch modifications are intended to be within the scope of the presentinvention, which is defined by the claims below.

[0159] All publications and patent applications mentioned in thisspecification are indicative of the level of skill of those in the artto which the invention pertains. All publications and patentapplications are herein incorporated by reference to the same extent asif each individual publication or patent application were specificallyand individually indicated to be incorporated by reference in itsentirety. The specifications of Application Serial No. 60/025,050, filedAug. 30, 1996, and PCT application PCT/US97/15272 (published applicationWO 98/08498), filed Aug. 29, 1997, are specifically incorporated byreference in their entireties.

What is claimed is:
 1. A method of treating a pathology that isameliorated by a modulation of CNS activity, comprising administering toa patient suffering from said pathology a compound selected from thegroup consisting of: isovaleric acid, a pharmaceutically acceptable saltof isovaleric acid, a pharmaceutically acceptable ester of isovalericacid, a pharmaceutically acceptable amide of isovaleric acid, and acompound having the structure:

wherein A=H, CH₃ or OH, B=H, OH, or CH₃, X=CH₂, CHCH₃, C(CH₃)₂, —O—,CH(OH)—, or —CH₂O—, Y=—CO—, or —SO₂—, and Z=H, CH₂CO₂H, or CH₂CONH₂, andwherein said compound is selected from the group consisting of2-methylisovaleramide, 3-methylisovaleramide, 2,2-dimethylisovaleramide,2,3-dimethylisovaleramide, 4-methylisovaleramide,2,4-dimethylisovaleramide, 3,4-dimethylisovaleramide,2,2,4-trimethylisovaleramide, 3-hydroxyisovaleramide,4-hydroxyisovaleramide, 4-hydroxy-3-methyl-isovaleramide,2-hydroxyisovaleramide, N-(2-acetamido)isovaleramide, 2-methyl-1-propylsulfonamide, 1-methylethyl sulfamate, 2-methyl-1-propyl sulfamate,isopropyl carbamate, and isobutylcarbamate, with the proviso that thetreated pathology is not convulsions when the compound is3-methylisovaleramide, isopropyl carbamate, or isobutyl carbamate.
 2. Amethod according to claim 1, wherein said pathology is convulsions.
 3. Amethod according to claim 1, wherein said pathology is spasticity.
 4. Amethod according to claim 1, wherein said pathology is an affective mooddisorder.
 5. A method according to claim 1, wherein said pathology is aneuropathic pain syndrome.
 6. A method according to claim 1, whereinsaid pathology is headache.
 7. A method according to claim 1, whereinsaid pathology is restlessness syndrome.
 8. A method according to claim1, wherein said pathology is a movement disorder.
 9. A method accordingto claim 1, wherein said pathology is substance abuse/craving.
 10. Amethod according to claim 1, wherein said compound is isovaleramide. 11.A method of providing neuroprotection to a patient suffering from acerebral insult, comprising administering to said patient atherapeutically effective amount of a compound selected from the groupconsisting of isovaleric acid, a pharmaceutically acceptable salt ofisovaleric acid, a pharmaceutically acceptable ester of isovaleric acid,a pharmaceutically acceptable amide of isovaleric acid, and a compoundhaving the structure:

wherein A=H, CH₃ or OH, B=H, OH, or CH₃, X=CH₂, CHCH₃, C(CH₃)₂, —O—,CH(OH)—, or —CH₂O—, Y=—CO—, or —SO₂—, and Z=H, CH₂CO₂H, or CH₂CONH₂ andwherein said compound is selected from the group consisting of 2-methylisovaleramide, 3-methylisovaleramide, 2,2-dimethylisovaleramide,2,3-dimethylisovaleramide, 4-methylisovaleramide,2,4-dimethylisovaleramide, 3,4-dimethylisovaleramide,2,2,4-trimethylisovaleramide, 3-hydroxyisovaleramide,4-hydroxyisovaleramide, 4-hydroxy-3-methyl-isovaleramide,2-hydroxyisovaleramide, N-(2-acetamido)isovaleramide, 2-methyl-1-propylsulfonamide, 1-methylethyl sulfamate, 2-methyl-1-propyl sulfamate,isopropyl carbamate, and isobutylcarbamate.
 12. A method according toclaim 11, wherein said compound is isovaleramide.
 13. A method oftreating a pathology that is ameliorated by a modulation of CNSactivity, comprising administering to a patient suffering from saidpathology an extract of Valerianaceae, cramp bark, black haw, or hops,wherein said extract comprises at least one compound that is hydrolyzedin vivo to yield isovaleric acid or isovaleramide.
 14. A methodaccording to claim 13, wherein said pathology is spasticity.
 15. Amethod according to claim 1, wherein said compound is 2-methylisovaleramide.
 16. A method according to claim 1, wherein said compoundis 3-methylisovaleramide.
 17. A method according to claim 1, whereinsaid compound is, 2,2-dimethylisovaleramide.
 18. A method according toclaim 1, wherein said compound is 2,3-dimethylisovaleramide.
 19. Amethod according to claim 1, wherein said compound is4-methylisovaleramide.
 20. A method according to claim 1, wherein saidcompound is 2,4-dimethylisovaleramide.
 21. A method according to claim1, wherein said compound is 3,4-dimethylisovaleramide.
 22. A methodaccording to claim 1, wherein said compound is2,2,4-trimethylisovaleramide.
 23. A method according to claim 1, whereinsaid compound is 3-hydroxyisovaleramide.
 24. A method according to claim1, wherein said compound is 4-hydroxyisovaleramide.
 25. A methodaccording to claim 1, wherein said compound is4-hydroxy-3-methyl-isovaleramide.
 26. A method according to claim 1,wherein said compound is 2-hydroxyisovaleramide.
 27. A method accordingto claim 1, wherein said compound is N-(2-acetamido)isovaleramide.
 28. Amethod according to claim 1, wherein said compound is 2-methyl-1-propylsulfonamide.
 29. A method according to claim 1, wherein said compound is1-methylethyl sulfamate.
 30. A method according to claim 1, wherein saidcompound is 2-methyl-1-propyl sulfamate.
 31. A method according to claim1, wherein said compound is, isopropyl carbamate.
 32. A method accordingto claim 1, wherein said compound is isobutylcarbamate